1 TECHNISCHE UNIVERSITÄT MÜNCHEN Klinik für Anaesthesiologie, Klinikum rechts der Isar Sugammadex and Neostigmine Dose-finding Study for Reversal of Residual Neuromuscular Block (SUNDRO-Study) Stefan Schaller Vollständiger Abdruck der von der Fakultät für Medizin der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Medizin genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. E. J. Rummeny Prüfer der Dissertation: 1. Priv.-Doz. Dr. H. Fink 2. Univ.-Prof. Dr. P. Tassani-Prell Die Dissertation wurde am 12.07.2011 bei der Technischen Universität München eingereicht und durch die Fakultät für Medizin am 18.09.2013 angenommen.
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TECHNISCHE UNIVERSITÄT MÜNCHEN
Klinik für Anaesthesiologie, Klinikum rechts der Isar
Sugammadex and Neostigmine Dose-finding Study for
Reversal of Residual Neuromuscular Block
(SUNDRO-Study)
Stefan Schaller
Vollständiger Abdruck der von der Fakultät für Medizin der Technischen Universität
München zur Erlangung des akademischen Grades eines
Doktors der Medizin
genehmigten Dissertation.
Vorsitzender: Univ.-Prof. Dr. E. J. Rummeny
Prüfer der Dissertation: 1. Priv.-Doz. Dr. H. Fink
2. Univ.-Prof. Dr. P. Tassani-Prell
Die Dissertation wurde am 12.07.2011 bei der Technischen Universität München eingereicht
und durch die Fakultät für Medizin am 18.09.2013 angenommen.
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Ich weiß, dass ich nichts weiß.
(Sokrates)
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Table of Contents List of Abbreviations .................................................................................................................. 4 1 Introduction ........................................................................................................................ 5
1.5 Aims of the Study ..................................................................................................... 11 2 Materials and Methods ..................................................................................................... 12
2.1 Study Design and Patient Selection ......................................................................... 12 2.2 Procedure .................................................................................................................. 12 2.3 Data Management and Statistical Analysis .............................................................. 14
List of Abbreviations AE Adverse Event AIC Akaike Information Criterion ASA American Society of Anesthesiology COO- Carboxy-group CRE Critical Respiratory Event ECG Electrocardiogram Max Maximum min Minutes Min Minimum mio Million ml Milliliter MRC Medical Research Council n.e. not estimable NMT Neuro Muscular Transmission PORC Postoperative Residual Curarization PTC Post-Tetanic Count SAE Serious Adverse Event smPC Summary of Product Characteristics SUNDRO Sugammadex and Neostigmine Dose-finding Study for Reversal of
Residual Neuromuscular Block TOF Train-of-Four
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1 Introduction
1.1 Historical View and Safety
Over the last years there has been tremendous improvement in patient safety as regards
anesthesia. This is reflected by a reduction of intraoperative mortality from approximately 1
in 10,000 in the 1980s to under 1 in 100,000 in the year 2000 (Gibbs 2005, p. 616; Hovi-
Viander 1980, p. 483; Lagasse 2002, p. 1609; Lienhart 2006, p. 1087). This improvement
may be credited not only to technical advances like intraoperative high-tech monitoring or
ventilation machines (Auroy 2009, p. 366) as well as structured training programs, but also to
pharmacological advances like short acting substances. These contributing factors to the
aforementioned improvement have led to a concept of (so-called) “balanced anesthesia”
(Tonner 2005, p. 475), a concept which connotes the combination of an anesthetic, an
analgesic and a muscle relaxant so as to induce (and maintain) general anesthesia. The
combination of different substances thereby reduces each substance’s individual amount and
consequently the unwanted effects otherwise implicated by these substances.
An integral element of (the concept of) balanced anesthesia are muscle relaxants. They
improve intubation conditions (Mencke 2003, p. 1049; Schlaich 2000, p. 720; Sparr 1997, p.
1300) and might even contribute to depth of anesthesia (Bonhomme 2007, p. 456). During the
overall improvement on patient safety it became evident that the ratio of intra- to post-
operative mortality is 1 to 1000 (Fink 2007, p. 1127; Henderson 2007, p. 1103); a
development which caused the researches to focus on potential unintended (and undesirable)
effects of muscle relaxation. A pharmacological action of muscle relaxation, beyond its
intended effect for induction of anesthesia and intraoperative surgical conditions, defined as
postoperative residual curarization (PORC) (Cammu 2002, p. 129; Debaene 2003, p. 1042;
Hayes 2001, p. 312; McCaul 2002, p. 766) can cause the following effects:
(1) respiratory insufficiency (Murphy 2008, p. 130),
(2) impaired upper airway function (Eikermann 2006, p. 937),
(3) increased risk of aspiration (Sundman 2000, p. 977), as well as (consecutively)
(4) the risk of postoperative pulmonary complications (Berg 1997, p. 1095).
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1.2 Muscle Relaxants
Muscle relaxation improves intubation conditions, which in turn lead to reduced postoperative
hoarseness and injuries of the vocal cords (Lieutaud 2003, p. 121; Masso 2006, p. 249;
Mencke 2003, p. 1049). Since airway injuries are a frequent cause for claims against
anesthesiologists (Cass 2004, p. 47), muscle relaxation is an imperative for modern balanced
anesthesia including intubation. In addition, muscle relaxants may potentially improve
surgical conditions – although there are no supporting studies available to date.
Muscle relaxants can be divided into:
1. depolarizing muscle relaxants (e.g. succinylcholine) and
2. nondepolarizing muscle relaxants
a. benzylisoquinolones (e.g. atracurium, cisatracurium and mivacurium)
b. aminosteroidal muscle relaxants (e.g. rocuronium, vecuronium and
pancuronium) (Blobner 2009, p. 105)
Succinylcholine (structurally a di-acetylcholine molecule) mimics the effect of acetylcholine
at the neuromuscular junction. It depolarizes the post-synaptic membrane, leading to an initial
fasciculation. Succinylcholine is the only depolarizing muscle relaxant in clinical use.
However, it has numerous unwanted effects such as life-threatening hyperkalemia, malignant
hyperthermia, as well as increased intraocular, gastric, and cerebral pressure (Blobner 2009,
p. 112).
Non-depolarizing muscle relaxants act by inducing a competitive blockade of the
acetylcholine receptor of the neuromuscular junction, thus inhibiting any physiologic
neuromuscular transmission.
The effects of muscle relaxants are evaluated by neuromuscular monitoring. Most frequently
a train-of-four stimulation pattern is used. For two seconds, four 2 Hz stimuli are applied to a
peripheral nerve, with the evoked muscle contraction recorded. The fourth contraction is then
set into relation to the first contraction, resulting in a train-of-four ratio. Complete muscle
paralysis occurs at a train-of-four ratio of zero. Recovery to a train-of-four ratio of 0.9 is
considered to be sufficient functional recovery by today’s standard.
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1.3 Postoperative Residual Curarization (PORC)
Although textbooks suggest muscle relaxants to have a predictable duration of effect
clinically, there is a wide inter-individual difference in duration of action, which leads to high
rates of PORC (Maybauer 2007, p. 12). PORC is defined as a train-of-four (TOF) ratio below
0.9 and is a common but largely underestimated problem. PORC leads to respiratory
insufficiency, impaired upper airway function and increased risk of aspiration, which leads to
an increased incidence of postoperative pulmonary complications if not treated properly.
In 1979 Viby-Mogensen showed (Viby Mogensen 1979, p. 539) that 42% of patient
admissions in the recovery room suffered from PORC (in those days defined as a TOF ratio
below 0.7). Unfortunately, patient safety has not improved as regards PORC, as in 2003 60%
of the patients in the recovery room still suffered PORC with a TOF ratio below 0.9 (Debaene
2003, p. 1042). Clinically, there is a high incidence of Critical Respiratory Events (CRE) in
patients with PORC (Murphy 2008, p. 130). However, clinical tests per se are not sufficient to
identify PORC. The only way to identify PORC and thereby effectively treat patients is by
neuromuscular monitoring (Baillard 2005, p. 622). And once PORC is identified, the residual
effects of muscle relaxants need to be reversed.
1.4 Reversal of Muscle Relaxants
1.4.1 Overview
Drugs used to reverse the effects of neuromuscular blocking drugs are divided into:
1. Antagonists
2. Encapsulators
1.4.2 Cholinesterase Inhibitors
Presynaptically released acetylcholine is degraded by acetylcholine esterase into acetate and
choline. Both choline and acetate are transported back into the presynaptic nerve terminal and
re-used to synthesize acetylcholine. Acetylcholine esterase is mostly located in the
extracellular matrix of the neuromuscular junction. As a result, most of the released
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acetylcholine is degraded right after its release. Inhibition of acetylcholine esterase therefore
increases the concentration of acetylcholine in the neuromuscular junction. Due to the
competitive mechanism of non-depolarizing muscle relaxants, an increase in acetylcholine
leads to a higher possibility of the agonist to bind at the receptor location, leading to restored
neuromuscular transmission. (Fink 2004, p. 573)
Two acetylcholine esterase inhibitors are currently used in Germany for reversal of
neuromuscular block:
1. neostigmine
2. pyridostigmine
Physiostigmine is not used to reverse neuromuscular block, since it crosses the brain-blood-
barrier. Its application is limited to act as a therapeutic agent for a central anticholinergic
syndrome.
Antagonists, however, have certain limitations. After blocking all present acetylcholine
esterase an additional dose of cholinesterase inhibitors will not produce a further effect
(ceiling effect). Therefore, a deep neuromuscular block cannot be antagonized with
acetylcholine esterase inhibitors. Secondly, acetylcholine esterase inhibitors do not selectively
act at the neuromuscular junction. They also increase acetylcholine in the autonomous
nervous system, leading to several side effects – in particular, bradycardia, rise in intraocular
pressure, increased bowel movement, increased contraction of the gall bladder, ureter and
detrusor muscle, relaxation of the bladder sphincter and increased sudoral secretion.
Therefore, acetylcholine esterase inhibitors are usually combined with parasympatholytic
drugs (e.g. atropine or glycopyrronium bromide) to decrease these unwanted side effects.
Parasympatholytic drugs, however, exert unwanted effects of their own, such as tachycardia
or dry mouth.
Neostigmine, which was used in this study, has a quaternary ammonium structure and is a
peripheral acting reversible cholinesterase inhibitor. It is not lipophilic and therefore does not
cross the blood brain barrier. It is poorly reabsorbed after oral intake, but is quickly
distributed after intravenous application. After application, a high concentration can be
measured in the liver and muscle tissue. Elimination half time after intravenous application
occurs between 24 and 80 minutes, a duration which increases under impaired renal function
(Blobner 2008, p. 342).
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Recommended doses of neostigmine for reversal of neuromuscular block vary from 20-
70 µg/kg bodyweight (Blobner 2009, p. 115). A ceiling effect is observed at approximately
60-80 µg/kg. Maximal antagonistic effect of neostigmine occurs in approximately ten
minutes. The recommended combination of neostigmine with a parasympatholytic agent is
1:2.5 for atropine or 1:5 for glycopyrronium bromide. In this study, glycopyrronium bromide
is used as it (in addition) does not cross the blood-brain-barrier and thus has a lower incidence
for postoperative cognitive deficits compared to atropine.
1.4.3 Encapsulator Sugammadex
Sugammadex is a modified γ-cyclodextrin which has been developed to reverse rocuronium
bromide-induced neuromuscular block. It has been available in Germany since October 2008.
Cyclodextrins are cyclic oligosaccharide molecules, which are known for their capability to
encapsulate lipohilic molecules. Cyclodextrins are divided into α-, β- and γ-cyclodextrins
dependent on their assembly of six, seven or eight glucose molecules. Characteristically, they
have a cylindrical form with a lipophilic cavity and a hydrophilic exterior part. Liphophilic
molecules can be encapsulated in the cavity and transported to a hydrophilic environment.
Sugammadex, however, is a synthetic γ-cyclodextrin where every sixth carbohydroxyl-group
is replaced by a thioether-side-chain with a negatively charged carboxy-group (COO-). This
leads to a larger cavity and allows encapsulating the muscle relaxants rocuronium (and, to a
lesser effective degree, vecuronium) (Bom 2009, p. 29; Welliver 2009, p. 49).
Encapsulation of rocuronium or vecuronium occurs in two phases:
1. After intravenous injection, all intravasal rocuronium/vecuronium-molecules are
encapsulated and by that, pharmacologically inactivated. This results in a
concentration gradient between plasma and extravasal space (including the
neuromuscular junction).
2. All extravasal rocuronium/vecuronium molecules are recruited back into the
bloodstream where they are immediately encapsulated and inactivated.
The binding shows a high stability based on electrostatic interaction between the positively
charged azotic molecules of rocuronium/vecuronium and the negatively charged carboxy-
groups of sugammadex. Van der Waals forces play a minor role in this interaction. The
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association-dissociation-rate of sugammadex and rocuronium is 25,000,000 to 1 – meaning,
while 25 million molecules of rocuronium are encapsulated, only one molecule dissociates
from sugammadex within the same time (Bom 2009, p. 30; Welliver 2009, p. 52). The
rocuronium-sugammadex complex is highly stable under alternating conditions as regards
temperature or pH, and is eliminated entirely via the kidney (normally within 8 hours).
Interestingly, the primary hepatic elimination of rocuronium is in this way replaced by a renal
elimination (together with sugammadex). Its elimination half-life period is approximately 100
minutes, calculated at a plasma clearance equal to the glomeric filtration rate of 120 ml/min
(Naguib 2007, p. 577; Sparr 2009, p. 69).
Because of the 1:1 interaction of the encapsulation, the reversal depends on adequate dosage.
The following doses are recommended in the Summary of Product Characteristics when used
for a reversal of rocuronium-induced block:
a. appearance of second twitch of TOF-stimulation (T2>0): 2 mg/kg
b. 1-2 post-tetanic counts after five seconds of tetanic stimulation (PTC 1-2): 4 mg/kg
c. immediate reversal of rocuronium-induced block: 16 mg/kg
Under these dosages, a TOF-ratio of 0.9 will be reached within two minutes on average (Sparr
2009, p. 70).
Compared to antagonists (like neostigmine) cyclodextrins have no intrinsic effect. Their most
common side effects consist in anesthetic complications (such as grimacing or coughing
against the intratracheal tube), intraoperative awareness, allergic reactions, or dysgeusia.
In pharmaco-kinetic/pharmaco-dynamic modeling, no interaction was found for 300
compounds commonly used during anesthesia. However, three drugs are identified where